(a) Field of the Invention
The invention relates to 12-hetero substituted 6,11-ethano-6,11-dihydrobenzo [b]quinolizinium salts, to compositions containing the same, to the method of use thereof in the treatment or prevention of neurodegenerative disorders or neurotoxic injuries and to a process for preparing intermediates.
(b) Information Disclosure Statement
Fields, U.S. Pat. No. 3,517,073 issued Jun. 23, 1970, discloses compounds of the formula: ##STR1## wherein each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 when taken separately, is hydrogen, lower alkyl, lower aryl, lower acyloxy, lower alkoxy, nitro, halogen, lower acylamino, di(lower alkyl) amino; one group of R.sup.1 and R.sup.2, R.sup.2 and R.sup.3, and R.sup.3 and R.sup.4, preferably R.sup.1 and R.sup.2, and R.sup.3 and R.sup.4, each group when taken together, represents a fused ring system containing up to three 6- member carbocyclic and nitrogen-containing heterocyclic rings at least one of which is an aromatic ring, and having no more than two nuclear nitrogens in any ring, which may be unsubstituted or substituted with one or more of the substituents defined by R.sup.1, R.sup.2, R.sup.3 and R.sup.4 ; each of R.sup.5 and R.sup.6, when taken separately is hydrogen, lower alkyl or lower aryl; each of R.sup.7 and R.sup.8 when taken separately, is hydrogen; R.sup.7 and R.sup.8, when taken together, represent a fused ring system as defined hereinbefore; R.sup.9, when taken individually, is methylene or lower alkyl, lower aryl, lower alkenyl, halogen, or cyano substituted methylene; R.sup.10, when taken individually, is a protected carbonyl group; R.sup.9 and R.sup.10, when taken together, represent a fused aromatic carbocyclic or heterocyclic ring system, whose valence bonds are from adjacent carbons, containing up to three 6-membered carbocyclic and nitrogen-containing heterocyclic rings having no more than two nitrogens in any ring and which may be substituted with one or more of the substituents defined by R.sup.1, R.sup.2, R.sup.3 and R.sup.4. Among the compounds specifically disclosed are 12,12-diethoxy-11-methyl-9,10-ethano-9,10-dihydro-4a-azoniaanthracene perchlorate and 9,10-(O-benzeno)-9,10-dihydro-5-methyl-4a-azoniaanthracene perchlorate. Also disclosed are compounds of the formula: ##STR2## wherein R.sup.1 -R.sup.10 are as defined above and m is an odd integer having a value of from 1 to 5, inclusive. Among the compounds specifically disclosed are 12,12-diethoxy-11-methyl-9,10-ethano-4a-aza-1,2,3,4,4a,9,9a,10-octahydroan thracene perchlorate acid salt, 9,10-(O-benzeno)-5-methyl-4a-aza-1,2,3,4,4a,9,9a,10-octahydroanthracene and 12,12-diethoxy-9,10-ethano-11-bromo-4a-aza-1,2,3,4,4a,9,9a,10-octahydr oanthracene. The above-described compounds are disclosed as being intermediates in the synthesis of 2-napthol derivatives and various anthracene derivatives.
Fields et al. , J. Org. Chem. 1968, 33 (1), 390-395, disclose a series of sixteen Dieis-Alder adducts prepared from a 4a-azoniaanthracene ion and various dienophiles. Among the compounds specifically disclosed are 12-ethyl, 12-hydroxymethyl and 12-ethylene-9,10-dihydro-4a-azonia-9,10-ethanoanthracene bromides; 12-phenyl-12-(4-morpholinyl), 12-methyl-12-(1-methylethylene), 12,12-diethoxy-11-bromo and 12-diethylamino-11-phenyl-9,10-dihydro-4a-azonia-9,10-ethanoanthracene perchlorates, as well as 9, 10[1',2']cyclopentyl and 9,10[2',3']tetrahydropyranyl-9,10-dihydro-4a-azoniaanthracene perchlorates. No utility is disclosed for these compounds.
Fields and Regan, J. Org. Chem. 1971, 36 (20), 2986-2990, disclose compounds of the formula: ##STR3## wherein R is H, Br, or OAc, as intermediates in the synthesis of substituted 8-tert-butyl-1-(2-pyridyl)napthalenes. Fields and Regan, J. Org. Chem. 1971, 36(20), 2991-2994, disclose compounds of the formula: ##STR4## wherein R is H, CH.sub.3, C.sub.6 H.sub.5, or Br, as intermediates in the synthesis of 2-pyridylnapthols. 0 Fields, J. Org. Chem. 1971, 36(20), 3002-3005, discloses a series of substituted 12,12-diethoxy-9,10-ethano-9,10-dihydro-4a-azoniaanthracenes and the corresponding derivatives wherein the pyridinium moiety is partially or completely reduced, as intermediates in the synthesis of substituted 2-napthols. Among the compounds specifically disclosed is 12,12-diethoxy-5,11-dimethyl-9,10-ethano-9,10-dihydro-4a-azoniaanthracene perchlorate. Also disclosed is a series of substituted 9,10-(O-benzeno)-9,10-dihydro-4a-azoniaanthracenes and the corresponding derivatives wherein the pyridinium moiety is partially or completely reduced, as intermediates in the synthesis of substituted anthracenes. Among the compounds specifically disclosed is 9,10-(O-benzeno)-9,10-dihydro-4a-azoniaanthracene perchlorate.
Westerman and Bradsher, J. Org. Chem. 1971, 36(7), 969-970, disclose compounds of the formula: ##STR5## wherein R is CH.sub.3, CH(CH.sub.3).sub.2, H, F, I, Cl, Br, CO.sub.2 H, CO.sub.2 CH.sub.3, or NO.sub.2. No utility is disclosed for these compounds.
Bradsher and Day, J. Het. Chem. 1973, 10, 1031-1033, disclose four Dieis-Alder adducts prepared from acridizinium perchlorate and cyclopentadiene, methyl vinyl ether, norbornadiene and maleic anhydride. No utility is disclosed for these compounds.
Fields and Regan, J. Org. Chem. 1970, 35 (6), 1870-1875, disclose compounds of the formula: ##STR6## wherein R is H, CH.sub.3 or C.sub.6 H.sub.5. Also specifically disclosed are 9,10-dihydro-12,12-dimethoxy-11,11-dimethyl-4a-azonia-9,10-ethanoanthracen e perchlorate and 9,10-dihydro-9,11-dimethyl-12,12-diethoxy-4a-azonia-9,10-ethanoanthracene perchlorate. The compounds are said to be intermediates in the synthesis of 9,10-dihydro-12-oxo-4a-azonia-9,10-ethanoanthracenes.
Fields et al., J. Org. Chem. 1971, 36 (20), 2995-3001, disclose 9,10-dihydro-4a-azonia-9,10-O-benzenoanthracene perchlorate and several analogs as intermediates in the synthesis of various 9- (2-pyridyl) anthracenes.
Fields and Miller, J. Het. Chem. 1970, 7, 91-97, disclose a compound of the formula: ##STR7## as an intermediate in the synthesis of the corresponding 5,8-dione salt.
Bradsher and Stone, J. Org. Chem. 1968, 33(2), 519-523, disclose a series of Dieis-Alder adducts prepared from an acridizinium ion and maleic anhydride, maleate esters, fumarate esters and various para-substituted styrenes in which the para substituent is H, CH.sub.3, OCH.sub.3 or NO.sub.2. No utility is disclosed for these compounds. A substantially similar disclosure for the preparation of Dieis-Alder adducts from acridizinium bromide and maleic anhydride, maleate or fumarate esters can be found in Bradsher and Solomons, J. Am. Chem. Soc. 1958, 80, 933-934.
Bradsher and Stone, J. Org. Chem. 1969, 34(6), 1700-1702, disclose compounds of the formula: ##STR8## wherein R is H, or CH.sub.3 ; R' is H, or CH.sub.3 ; R" is OCH.sub.3, CH.sub.3, H, or NO.sub.2 ; and X-- is perchlorate; without an indication of utility. Also disclosed are the Dieis-Alder adduces obtained from acridizinium perchlorate and diethyl maleate, diethyl fumarate or dimethyl maleate, without an indication of utility.
Burnham and Bradsher, J. Org. Chem. 1972, 37(3), 355-358, disclose compounds of the formula: ##STR9## wherein R.sup.1 is Ph, and R.sup.2 is OEt; or R.sup.1 is H, and R.sup.2 is OEt, OBu, OAc, N-carbazolyl or 1-pyrrolidin-2-one, without an indication of utility
Parham et al., J. Org. Chem. 1972, 37(3), 358-362, disclose compounds of the formula: ##STR10## wherein R is H.sub.2, (CH.sub.2).sub.3, C(O)NHC(O), C(O)N(CH.sub.3)C(O), C(O)OC(O), CH.sub.2 OCH.sub.2, or CH.sub.2 NH.sub.2 +CH.sub.2, without an indication of utility.
Bradsher et al., J. Am. Chem. Soc. 1977, 99(8), 2588-2591, disclose compounds of the formula: ##STR11## wherein: R.sup.1 =R.sup.2 =R.sup.4 =R.sup.5 =H; R1=Me, and R.sup.2 =R.sup.4 =R.sup.5 =H, R.sup.1 =R.sup.4 =R.sup.5 =H, and R.sup.2 =Me; and R.sup.1 =H, and R.sup.2 =R.sup.4 =R.sup.5 =Me. No utility is disclosed for these compounds.
Bradsher et al., J. Org. Chem. 1978, 43 (5), 822-827, disclose compounds of the formula: ##STR12## wherein: R.sup.1 is OEt and R is Me, H, F, Cl, CO.sub.2 Me or NO.sub.2 ; R.sup.1 is O-Ph-p-X, wherein X is CH.sub.3, OCH.sub.3, H, C(O)CH.sub.3, or NO.sub.2, and R is hydrogen; and R.sup.1 is N-carbazolyl and R is hydrogen. No utility is disclosed for these compounds.
Westerman and Bradsher, J. Org. Chem. 1978, 43(15), 3002-3006, disclose a series of Diels-Alder adducts prepared from an acridizinium ion and various unsymmetrical alkenes, without an indication of utility. Among the compounds specifically disclosed are 6,11[2',3']indanyl-6,11-dihydroacridizinium tetrafluoroborate, and 12-phenyl-13-(2-pyridyl)-6,11-dihydro-6,11-ethanoacridizinium tetrafluoroborate.
Westerman and Bradsher, J. Org. Chem. 1979, 44 (5), 727-733, disclose a series of Dieis-Alder adducts prepared from a substituted or unsubstituted acridizinium cation and various polarizable alkenes without an indication of utility. Among the compounds specifically disclosed are 12,12-diphenyl-6,11-dihydro-6,11-ethanoacridizinium perchlorate or bromide, 9-methyl-6,11[2',3']indanyl-6,11-dihydroacridizinium tetrafluoroborate, and 7,10-dimethyl-12-phenyl-12-(4-morpholinyl), 9-methyl-12-phenyl-12-(4-morpholinyl), 12-(2-pyridyl), and 9-methyl-12-(2-pyridyl)-6,11-dihydro-6,11-ethanoacridizinium tetrafluoroborates.
Bradsher et al., J. Org. Chem. 1979, 44 (8), 1199-1201, disclose a series of Dieis-Alder adducts prepared from a substituted or unsubstituted acridizinium ion and cyclopropene or 1-methylcyclopropene, without an indication of utility.
Hart et al., Tetrahedron Letters 1975, 52, 4639-4642, disclose a compound of the formula: ##STR13## as an intermediate in the synthesis of 1,4,5,8, 9-pentamethylanthracene.